Ophthalmological aqueous composition

ABSTRACT

The present invention provides an aqueous ophthalmic composition having a pH of 7 or more, containing a terpenoid and zinc chloride. According to the present invention, an aqueous ophthalmic composition is provided in which adsorption of the terpenoid to a container can be inhibited, thereby making it possible to inhibit the reduction in the terpenoid content for a long period of time, the aqueous ophthalmic composition having some excellent actions such as an inhibitory action for histamine release, and an inhibitory action for discharges from the eyes.

TECHNICAL FIELD

The present invention relates to an aqueous ophthalmic composition. Moreparticularly, the present invention relates to an aqueous ophthalmicsolution in which adsorption of a terpenoid to a container is inhibited,and a method for inhibiting adsorption of a terpenoid to a container inan aqueous ophthalmic composition.

BACKGROUND ART

In ophthalmic compositions, a terpenoid such as menthol is contained inorder to give a refreshing feel. However, when an ophthalmic compositioncontaining a terpenoid is filled in a plastic container or the like, theterpenoid adsorbs to the container during storage, so that the contentof the terpenoid is reduced. The reduction in the content of theterpenoid has some disadvantages of impairing feel of use because thereduction greatly influences the senses of the ophthalmic compositions,and further impairing qualities of the ophthalmic compositions. On theother hand, a method of inhibiting adsorption of a terpenoid to aplastic container by adding a surfactant (Patent Publications 1 and 2).However, surfactants may irritate ocular mucous membranes, so that it issaid that some side effects are caused, such as disorders are caused inthe cornea if, for example, eye drops containing surfactants arefrequently dropped or if individuals having disorders in the cornea orindividuals whose tear flow is not normal showing dry eye symptoms andthe like are dropped, so that there are some concerns in the aspect ofsafety.

On the other hand, a zinc salt such as zinc sulfate or zinc lactate hasconstrictive actions and anti-inflammatory actions, and has been usedwidely in eye drops as constrictive agents and anti-inflammatory agents,and zinc chloride or zinc sulfate has also been known as a bactericidalagent. However, the influences which these components would have on theaqueous ophthalmic compositions containing terpenoids have not beenelucidated.

PRIOR ART REFERENCES Patent Publications

-   Patent Publication 1: Japanese Patent Laid-Open No. 2002-003364-   Patent Publication 2: Japanese Patent Laid-Open No. 2005-162747

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention has been accomplished in view of the currentsituations of the prior art mentioned above, and an object thereof is toprovide an aqueous ophthalmic composition containing a terpenoid, theaqueous ophthalmic composition capable of inhibiting the adsorption ofterpenoids to the container, thereby maintaining a high residual ratioof terpenoids in the aqueous ophthalmic composition, and further toprovide a method for inhibiting the adsorption of the terpenoidscontained in the aqueous ophthalmic composition.

Furthermore, another object of the present invention is to provide anaqueous ophthalmic composition having other more improved actions.

Means to Solve the Problems

The present inventor has made intensive studies in order to accomplishthe objects mentioned above. As a result, it has been found that in theaqueous ophthalmic composition having a pH of 7 or more, containing zincchloride together with a terpenoid, the adsorption of the terpenoid tothe container can be inhibited when the aqueous ophthalmic compositionis filled in various containers such as plastic containers and stored,thereby making it possible to inhibit the reduction in the terpenoidcontent for a long period of time. In addition, the present inventor hasfound that the aqueous ophthalmic composition containing the aboveingredients markedly has an inhibitory action for histamine release, andfurther has an unexpected action of effectively inhibiting dischargesfrom the eyes. The present invention has been perfected as a result offurther studies based on these findings.

In other words, the present invention provides an aqueous ophthalmiccomposition of the embodiments listed hereinbelow.

Item 1-1: An aqueous ophthalmic composition having a pH of 7 or more,containing a terpenoid and zinc chloride.Item 1-2: The aqueous ophthalmic composition according to the above item1-1, wherein the terpenoid is at least one member selected from thegroup consisting of menthol, menthone, camphor, borneol, and geraniol.Item 1-3. The aqueous ophthalmic composition according to the item 1-1or 1-2, wherein the content proportion of the terpenoid in total is from0.00001 to 0.2 w/v %, on the basis of a total amount of the aqueousophthalmic composition.Item 1-4: The aqueous ophthalmic composition according to any one of theabove items 1-1 to 1-3, wherein the zinc chloride is contained in anamount of from 0.000005 to 5,000 parts by weight, based on 1 part byweight of a total amount of the terpenoids.Item 1-5: The aqueous ophthalmic composition according to any one of theabove items 1-1 to 1-4, further comprising a surfactant.Item 1-6: The aqueous ophthalmic composition according to any one of theabove items 1-1 to 1-5, further comprising a cellulose-based polymericcompound.Item 1-7: The aqueous ophthalmic composition according to any one of theabove items 1-1 to 1-6, wherein the composition is housed in a containermade of a material containing at least one plastic selected from thegroup consisting of polyethylene terephthalate resins, polypropyleneresins, polyethylene resins, and polyethylene naphthalate resins.

Also, the present invention provides a method for inhibiting adsorptionof a terpenoid to a container in the aqueous ophthalmic composition, ora method for inhibiting the reduction in the content of a terpenoid, ofthe embodiments listed hereinbelow.

Item 2-1: A method for inhibiting adsorption of a terpenoid to acontainer in an aqueous ophthalmic composition having a pH of 7 or more,including combining in the aqueous ophthalmic composition zinc chloridetogether with a terpenoid.Item 2-2: A method for inhibiting the reduction in the content of aterpenoid in an aqueous ophthalmic composition having a pH of 7 or more,including combining in the aqueous ophthalmic composition zinc chloridetogether with a terpenoid.

Further, the present invention also provides a method for enhancing aninhibitory action for histamine release of the aqueous ophthalmiccomposition, or a method for giving an inhibitory action for dischargesfrom the eyes to the aqueous ophthalmic composition, of the embodimentslisted hereinbelow.

Item 3-1. A method for enhancing an inhibitory action for histaminerelease of an aqueous ophthalmic composition having a pH of 7 or more,including combining in the aqueous ophthalmic composition a terpenoidand zinc chloride.Item 3-2. A method for giving an inhibitory action for discharges fromthe eyes to the aqueous ophthalmic composition having a pH of 7 or more,including combining in the aqueous ophthalmic composition a terpenoidand zinc chloride.

Further, the present invention also provides a method for inhibiting ortreating itchiness of the eyes, or a method for inhibiting dischargesfrom the eyes, of the embodiments listed hereinbelow.

Item 4-1. A method for inhibiting or treating itchiness of the eyes,including contacting an aqueous ophthalmic composition having a pH of 7or more, containing a terpenoid and zinc chloride, with cornea and/orconjunctiva.Item 4-2. A method for inhibiting discharges from the eyes, includingcontacting an aqueous ophthalmic composition having a pH of 7 or more,containing a terpenoid and zinc chloride, with cornea and/orconjunctiva.

Further, the present invention also provides use of the embodimentslisted hereinbelow.

Item 5. Use of a terpenoid and zinc chloride, in the manufacture of anaqueous ophthalmic composition having a pH of 7 or more, containing aterpenoid and zinc chloride, the aqueous composition having an actionfor inhibiting adsorption to a container of a terpenoid, an enhancedinhibitory action for histamine release, or an inhibitory action fordischarges from the eyes.

Further, the present invention also provides use of the embodimentslisted hereinbelow.

Item 6-1. Use of a composition having a pH of 7 or more, containing aterpenoid and zinc chloride, as an aqueous ophthalmic composition havingan action for inhibiting adsorption to a container of a terpenoid, anenhanced inhibitory action for histamine release, or an inhibitoryaction for discharges from the eyes.Item 6-2. Use according to the above item 6-1, wherein the compositionis a composition as defined in any one of the above items 1-2 to 1-7.

Further, the present invention also provides a composition of theembodiments listed hereinbelow.

Item 7-1. An aqueous composition having a pH of 7 or more, containing aterpenoid and zinc chloride, for use in an aqueous ophthalmiccomposition having an action for inhibiting adsorption to a container ofa terpenoid, an enhanced inhibitory action for histamine release, or aninhibitory action for discharges from the eyes.Item 7-2. The composition according to the above item 7-1, wherein thecomposition is a composition as defined in any one of the above items1-2 to 1-7.

Further, the present invention also provides a method for producing anaqueous ophthalmic composition of the embodiments listed hereinbelow.

Item 8-1. A method for producing an aqueous ophthalmic compositionhaving an action for inhibiting adsorption to a container of aterpenoid, an enhanced inhibitory action for histamine release, or aninhibitory action for discharges from the eyes, including adding aterpenoid and zinc chloride to a carrier containing water, to provide anaqueous composition having a pH of 7 or more.Item 8-2. The method according to the above item 8-1, wherein thecomposition is a composition as defined in any one of the above items1-2 to 1-7.

Effects of the Invention

According to the aqueous ophthalmic composition of the presentinvention, in an aqueous ophthalmic composition containing a terpenoid,the adsorption of the terpenoid to the container is inhibited, so thatthe reduction in the content of the terpenoid can be inhibited in theaqueous ophthalmic composition over a long period of time even during,for example, distribution process and the like. Since the reduction inthe terpenoid content in the aqueous ophthalmic composition greatlyaffects feel of use, the compliance of patients can also be improved byinhibiting the reduction in the terpenoid content.

Further, the aqueous ophthalmic composition of the present invention hasan excellent action of inhibiting histamine release. Accordingly, thecomposition of the present invention is used as an eye drop or aneyewash to contact the composition with cornea by a method such asdropping or eye-washing, thereby anti-histamine action is enhanced, sothat the itchiness of the eyes can be inhibited or treated. Therefore,the aqueous ophthalmic composition of the present invention is useful asan eye drop or eyewash for inhibiting itchiness, and the composition isfurther useful as eye drops or the like for allergies, for inflammation,or for dry eyes, for wearing or putting on contact lens that accompanyitchy symptoms.

In addition, the aqueous ophthalmic composition of the present inventionhas an action of effectively inhibiting discharges from the eyes.Accordingly, the composition of the present invention is contacted withcornea by a method such as dropping or eye-washing, whereby the amountof discharges from the eyes can be inhibited against patients showingsymptoms of discharges from the eyes, so that, for example, ease inopening eyes, ease in blinking, blurriness of eyes, or the like can beameliorated.

MODES FOR CARRYING OUT THE INVENTION 1. Aqueous Ophthalmic Composition

The aqueous ophthalmic composition of the present invention is anaqueous composition having a pH of 7 or more, containing a terpenoid andzinc chloride.

The term “aqueous composition” as used herein is a compositioncontaining water. The content proportion of water in the aqueousophthalmic composition of the present invention is, for example, from 10to 99.8 w/v %, preferably from 55 to 99.0 w/v %, more preferably from 70to 98.0 w/v %, even more preferably from 85 to 98.0 w/v %, andespecially preferably from 90 to 98.0 w/v %, on the basis of a totalamount of the hydrophobic ophthalmic composition.

The aqueous ophthalmic composition of the present invention will beexplained concretely hereinbelow.

(1) Terpenoid

The terpenoid is a known compound having a structure having an isopreneunit as a constituting unit, which has been used as a cooling agent.

In the aqueous ophthalmic composition of the present invention, theterpenoid can be used without particular limitations so long as theterpenoid is pharmacologically (pharmaceutically) or physiologicallyacceptable in the field of medicine. The terpenoid as described aboveconcretely includes menthol, menthone, camphor, borneol, geraniol,cineol, citronellol, carvone, anethole, eugenol, limonene, linalool,linalyl acetate, derivatives thereof, and the like. These compounds maybe in any of d-form, l-form, and dl-form.

In addition, in the present invention, an essential oil containing theabove compound may be used as a terpenoid. The essential oil asmentioned above includes, for example, eucalyptus oil, bergamot oil,peppermint oil, cool-mint oil, spearmint oil, Japanese mint oil, fenneloil, cinnamon oil, rose oil, camphor oil, and the like. These terpenoidsmay be used alone, or two or more kinds may be optionally combined andused.

Among these terpenoids, menthol, menthone, camphor, borneol, geraniol,and the like are preferred, menthol and camphor are more preferred,l-menthol, dl-menthol, d-camphor, and dl-camphor are even morepreferred, and l-menthol is especially preferred.

The content proportion of the terpenoid in the aqueous ophthalmiccomposition of the present invention can be appropriately set dependingupon the concrete kinds of the ophthalmic composition. As one example,the content proportion of the terpenoid is in total from 0.00001 to 0.5w/v %, preferably from 0.0005 to 0.25 w/v %, and more preferably from0.001 to 0.1 w/v %, on the basis of a total amount of the aqueousophthalmic composition. In addition, it is needless to say that thecontent proportion can be increased or decreased, by the number ofadministration, the method of administration, or the like.

(2) Zinc Chloride

In the aqueous ophthalmic composition of the present invention, zincchloride is combined together with a terpenoid, thereby inhibitingadsorption of a terpenoid to a plastic container, so that the reductionin the content of the terpenoid can be inhibited in the aqueousophthalmic composition over a long period of time. Further, the aqueousophthalmic composition of the present invention has an excellent actionsuch as an action for inhibiting histamine release or an action forinhibiting discharges from the eyes, so that some effects such asenhancement of anti-histamine action and inhibition of the amount ofdischarges from the eyes are exhibited by the use of the aqueousophthalmic composition.

Zinc chloride can be used without particular limitations, so long aszinc chloride can be used in the aqueous ophthalmic composition. Forexample, zinc chloride as prescribed in The Japanese PharmacopeiaSixteenth Edition can be used.

The content proportion of the zinc chloride in the aqueous ophthalmiccomposition of the present invention is not particularly limited. As oneexample, the content proportion of the zinc chloride is from 0.000001 to0.05 w/v %, preferably from 0.00005 to 0.025 w/v %, and more preferablyfrom 0.0001 to 0.015 w/v %, on the basis of a total amount of theaqueous ophthalmic composition.

In addition, the content proportion of zinc chloride based on thecontent of the terpenoid contained in the aqueous ophthalmic compositionis not particularly limited, and, for example, zinc chloride is in anamount of from 0.000005 to 5,000 parts by weight, preferably from 0.0005to 1,000 parts by weight, more preferably from 0.002 to 500 parts byweight, especially preferably from 0.002 to 10 parts by weight, and mostpreferably from 0.002 to 1 part by weight, based on 1 part by weight ofa total amount of the terpenoid, contained in the aqueous ophthalmiccomposition.

(3) pH of Aqueous Ophthalmic Composition

In the aqueous ophthalmic composition of the present invention, when apH value of the aqueous ophthalmic composition is 7 or more, adsorptionof the terpenoid to a container can be inhibited, and further givesactions such as enhancement of inhibitory effects for histamine releaseand inhibition of discharges from the eyes, by combining zinc chloridetogether with the terpenoid. The concrete pH value is varied dependingon intended applications, usage form, and the like, and the pH is, forexample, from 7 to 9.5, preferably from 7 to 9, and more preferably from7 to 8.5.

In the aqueous ophthalmic composition of the present invention, anadjustment of a pH can be performed using the above pH adjustment agent,buffer or the like.

(4) Surfactant

The aqueous ophthalmic composition of the present invention contains aterpenoid and zinc chloride, and the aqueous ophthalmic composition canoptionally contain a surfactant. Since the aqueous ophthalmiccomposition contains a surfactant, the effects of the present invention,in other words, the effects such as inhibition of adsorption of theterpenoid to the container, enhancement of inhibitory action forhistamine release, and inhibition of discharges from the eyes are moreremarkably exhibited.

The surfactant which can be contained in the aqueous ophthalmiccomposition of the present invention is not particularly limited, withthe limit of being pharmacologically (pharmaceutically) orphysiologically acceptable in the field of medicine, and the surfactantmay be any one of nonionic surfactants, amphoteric surfactants, anionicsurfactants, and cationic surfactants. Among them, concrete examples ofthe nonionic surfactants include POE sorbitan fatty acid esters such asPOE(20) sorbitan monolaurate (Polysorbate 20), POE(20) sorbitanmonopalmitate (Polysorbate 40), POE(20) sorbitan monostearate(Polysorbate 60), POE(20) sorbitan tristearate (Polysorbate 65), andPOE(20) sorbitan monooleate (Polysorbate 80); POE-POP block copolymerssuch as Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403,Poloxamer 237, and Poloxamer 124; POE hydrogenated castor oils such asPOE(60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil60); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl etherssuch as POE(20)POP(4) cetyl ether; POE alkyl phenyl ethers such asPOE(10) nonyl phenyl ethers; and the like. Here, in the compoundsexemplified above, POE stands for polyoxyethylene, POP stands forpolyoxypropylene, and the numbers inside parentheses stand for thenumber of moles added. In addition, the amphoteric surfactants which canbe contained in the aqueous ophthalmic composition of the presentinvention are concretely exemplified by alkyldiaminoethyl glycines, andthe like. In addition, the cationic surfactants which can be containedin the aqueous ophthalmic composition of the present invention areconcretely exemplified by benzalkonium chloride, benzethonium chloride,and the like. Also, the anionic surfactants which can be contained inthe aqueous ophthalmic composition of the present invention areconcretely exemplified by alkylbenzenesulfonates, alkyl sulfates,polyoxyethylene alkyl sulfates, α-sulfomethyl esters of fatty acids,α-olefinsulfonates, and the like.

In the aqueous ophthalmic composition of the present invention, thesurfactants may be used in a single kind alone or in a combination oftwo or more kinds.

The content proportion of the surfactant in the aqueous ophthalmiccomposition of the present invention is not particularly limited, and asone embodiment, the content proportion of the surfactant in a totalamount is preferably from 0.001 to 5 w/v %, more preferably from 0.01 to1 w/v %, and even more preferably from 0.03 to 0.5 w/v %, on the basisof a total amount of the aqueous ophthalmic composition.

More specifically, the following content proportions are exemplified.

In a case where the surfactant is a nonionic surfactant, the contentproportion of the nonionic surfactant in a total amount is preferablyfrom 0.001 to 2 w/v %, more preferably from 0.01 to 1 w/v %, and evenmore preferably from 0.03 to 0.5 w/v %, on the basis of a total amountof the aqueous ophthalmic composition.

In a case where the surfactant is a amphoteric surfactant, the contentproportion of the amphoteric surfactant in a total amount is preferablyfrom 0.001 to 1 w/v %, more preferably from 0.005 to 0.5 w/v %, and evenmore preferably from 0.01 to 0.1 w/v %, on the basis of a total amountof the aqueous ophthalmic composition.

In a case where the surfactant is an anionic surfactant, the contentproportion of the anionic surfactant in a total amount is preferablyfrom 0.001 to 2 w/v %, more preferably from 0.01 to 1 w/v %, and evenmore preferably from 0.03 to 0.5 w/v %, on the basis of a total amountof the aqueous ophthalmic composition.

In a case where the surfactant is a cationic surfactant, the contentproportion of the cationic surfactant in a total amount is preferablyfrom 0.001 to 1 w/v %, more preferably from 0.005 to 0.5 w/v %, and evenmore preferably from 0.01 to 0.1 w/v %, on the basis of a total amountof the aqueous ophthalmic composition.

(5) Polymeric Compound

Also, the aqueous ophthalmic composition of the present invention canoptionally contain a polymeric compound. Since the aqueous ophthalmiccomposition contains a polymeric compound, the effects of the presentinvention, in other words, the effects such as inhibition of adsorptionof the terpenoid to the container, enhancement of inhibitory action forhistamine release, and inhibition of discharges from the eyes are moreremarkably exhibited. The polymeric compounds may be used in a singlekind alone or in a combination of two or more kinds.

As a polymeric compound, for example, a cellulose-based polymericcompound can be used. As the cellulose-based polymeric compound,cellulose, a cellulose derivative in which a hydroxy group of thecellulose is substituted with another functional group, a salt thereof,or the like can be used.

Concrete examples of the cellulose derivative include methyl cellulose,ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose (hypromellose),carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxyethylcellulose, and the like.

The salts of the cellulose and derivatives thereof are not particularlylimited, so long as the salts are pharmacologically (pharmaceutically)or physiologically acceptable in the field of medicine. The salts can beexemplified by alkali metal salts such as sodium salts and potassiumsalts.

Among the cellulose-based polymeric compounds, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, andcarboxymethyl cellulose sodium are preferred, and hydroxypropylmethylcellulose and hydroxyethyl cellulose are more preferred.

These cellulose-based polymeric compounds may be used as a single kindalone, or in a combination of two or more kinds.

Here, the content proportion of the cellulose-based polymeric compoundis such that a total amount of the cellulose-based polymeric compoundsis from 0.0001 to 10 w/v %, preferably from 0.0025 to 7 w/v %, morepreferably from 0.005 to 5 w/v %, especially preferably from 0.01 to 3w/v %, and most preferably from 0.05 to 2.5 w/v % or so, on the basis ofa total amount of the aqueous ophthalmic composition.

In addition, the content proportion of the cellulose-based polymericcompound to the content of zinc chloride is such that, for example, atotal amount of the cellulose-based polymeric compounds is preferablyfrom 0.002 to 100,000 parts by weight, more preferably from 0.5 to60,000 parts by weight, and even more preferably from 2 to 30,000 partsby weight, based on 1 part by weight of zinc chloride.

(6) Other Components

The aqueous ophthalmic composition can selectively contain variouspharmacologically active components and physiologically activecomponents according to the conventional methods, depending upon theapplications and formulation forms thereof, within the range that wouldnot impair the effects of the present invention.

Further, the aqueous ophthalmic composition of the present invention cancontain various additives according to the conventional methods,depending upon the applications and formulation forms thereof, withinthe range that would not impair the effects of the present invention.

As the other components, boric acid and/or a salt thereof, for example,borax and the like, and sodium chloride are especially preferable.

(7) Method of Preparation and Applications of Aqueous OphthalmicComposition

The aqueous ophthalmic composition of the present invention may be anyaqueous composition having a pH of 7 or more, containing a terpenoid andzinc chloride, without particular limitations, and the aqueouscomposition can be prepared according to a method known to one ofordinary skill in the art. For example, the aqueous composition can beproduced by dissolving each of the components in a proper amount ofpurified water, thereafter adjusting to a given pH value, andsubsequently adding the remaining purified water to adjust its volume.In addition, the aqueous composition may also be optionally subjected tofiltration and sterilization treatment, and then filled to thecontainer.

Therefore, from another aspect, the present invention provides a methodfor producing an aqueous ophthalmic composition having an action ofinhibiting adsorption of the terpenoid to a container, an enhancedinhibitory action for histamine release, and an inhibitory action fordischarges from the eyes, including adding a terpenoid and zinc chlorideto a carrier containing water, to provide an aqueous composition havinga pH of 7 or more.

The aqueous ophthalmic composition of the present invention can be usedas formulations such as medicaments and quasi-drugs, including eye drops[the eye drops including eye drops which can be instilled into the eyeswhile wearing contact lenses], artificial tears, eyewashes [theeyewashes including eyewashes which can wash the eyes while wearingcontact lenses], compositions for contact lenses [solutions for wearingcontact lenses, compositions for contact lenses care (disinfectantsolutions for contact lens, storage solutions for contact lens,cleansing solutions for contact lenses, cleansing-storage solutions forcontact lenses), and the like], and the like. One preferred example ofthe aqueous ophthalmic composition of the present invention includes eyedrops, artificial tears, eyewashes, and solutions for wearing contactlenses, and especially preferred example includes eye drops andartificial tears. Here, when used as compositions for contact lenses,the aqueous ophthalmic composition is applicable to all sorts of contactlenses, including hard contact lenses and soft contact lenses.

The aqueous ophthalmic composition of the present invention can beprovided by housing the aqueous ophthalmic composition in any sorts ofcontainers. The container for housing the aqueous ophthalmic compositionof the present invention is not particularly limited, and any containermade of materials that can be used in a general container in the fieldof the art may be used, and, for example, glass materials and plasticmaterials, e.g. polyethylene terephthalate resin, polypropylene resin,polyethylene resin, polyethylene naphthalate resin, and the like, may beproperly selected and used according to their purposes and applications.In addition, the container for housing the aqueous ophthalmiccomposition of the present invention may be a transparent container inwhich the internal of the container can be visually recognized, or anopaque container which is difficult to visually recognize the internal.Since the confirmation of the amount of the solution of the aqueousophthalmic composition, foreign objects tests during the productionsteps, and the like is facilitated, especially transparent containersare preferred. Here, the term “transparent container” includes bothcolorless transparent containers and colored transparent containers.

The aqueous ophthalmic composition of the present invention canespecially remarkably inhibit the reduction in the content of theterpenoid by adsorption of the terpenoid to the container, even when theaqueous ophthalmic composition is housed in a plastic container which ismore likely to cause adsorption of the terpenoid in the conventionalaqueous ophthalmic composition. For this reason, the aqueous ophthalmiccomposition of the present invention is highly useful as an aqueousophthalmic composition used after housing in a plastic container, andespecially highly useful as an aqueous ophthalmic composition housed ina container made of a material including a polyethylene terephthalateresin or polyethylene resin to which terpenoid is more likely to beadsorbed.

Further, the aqueous ophthalmic composition of the present invention isprovided not only as a package form of “fully use at once” type, butalso is useful as an aqueous ophthalmic composition of multi-dose whichis a package in the form that is administered over plural times, and theuser continuously doses.

2. Method for Inhibiting Adsorption of Terpenoid in Aqueous OphthalmicComposition to Container

As mentioned above, since in the aqueous ophthalmic composition zincchloride and are combined together with a terpenoid, the terpenoidcontained in the aqueous ophthalmic composition having a pH of 7 or morecan be inhibited from being adsorbed to a container, such as a plasticcontainer, especially a container made of polyethylene terephthalate,thereby inhibiting the reduction in the terpenoid content in the aqueousophthalmic composition.

Therefore, from another aspect, the present invention provides a methodfor inhibiting adsorption of the terpenoid in the aqueous ophthalmiccomposition having a pH of 7 or more to a container, or a method forinhibiting the reduction in the content of the terpenoid, includingcombining in the aqueous ophthalmic composition of the present inventionzinc chloride together with a terpenoid.

Further, from another aspect, the present invention provides use of aterpenoid and zinc chloride, in the manufacture of an aqueous ophthalmiccomposition having a pH of 7 or more, containing a terpenoid and zincchloride, the aqueous composition having an action for inhibitingadsorption of the terpenoid to a container.

Further, from another aspect, the present invention provides use of acomposition having a pH of 7 or more, containing a terpenoid and zincchloride, as an aqueous ophthalmic composition having an action forinhibiting adsorption of the terpenoid to a container.

Further, from another aspect, the present invention provides an aqueouscomposition having a pH of 7 or more, containing a terpenoid and zincchloride, for use in an aqueous ophthalmic composition having an actionfor inhibiting adsorption of the terpenoid to a container.

In these methods, use, and compositions, so long as the terpenoid andzinc chloride are co-present in an aqueous ophthalmic composition, andthe order of addition of those components are not particularly limited.The terpenoid and zinc chloride may be those that can be combined in theaqueous ophthalmic composition of the present invention, and amountsthereof may be amount that can be combined in the aqueous ophthalmiccomposition of the present invention. Also, the kinds and contents ofeach of the components combined in the aqueous ophthalmic composition,the kinds and contents of the other components combined, formulationforms of the composition, and the like are the same as the aqueousophthalmic composition of the present invention.

3. Method for Enhancing Inhibitory Action for Histamine Release andMethod for Inhibiting or Treating Itchiness of the Eyes

Further, as mentioned above, by providing an aqueous ophthalmiccomposition having a pH of 7 or more, containing a terpenoid and zincchloride, inhibitory action for histamine release in the aqueousophthalmic composition can be enhanced.

Accordingly, from another aspect, the present invention provides amethod for enhancing inhibitory action for histamine release of anaqueous ophthalmic composition having a pH of 7 or more, includingcombining in the aqueous ophthalmic composition a terpenoid and zincchloride.

Further, from another aspect, the present invention provides use of aterpenoid and zinc chloride, in the manufacture of an aqueous ophthalmiccomposition having a pH of 7 or more, containing a terpenoid and zincchloride, the aqueous composition having an enhanced inhibitory actionfor histamine release.

Further, from another aspect, the present invention provides use of anaqueous composition having a pH of 7 or more, containing a terpenoid andzinc chloride, as an aqueous ophthalmic composition having an enhancedinhibitory action for histamine release.

Further, from another aspect, the present invention provides an aqueouscomposition having a pH of 7 or more, containing a terpenoid and zincchloride, for use in an aqueous ophthalmic composition having anenhanced inhibitory action for histamine release.

In addition, as mentioned above, by contacting the aqueous ophthalmiccomposition of the present invention with the cornea and/or conjunctivaby a method such as eye dropping or washing eyes using the compositionas eye drops or eyewashes, the action for inhibiting histamine releaseis enhanced, and whereby consequently anti-histamine action is enhanced,so that itchiness of the eyes can be inhibited or treated.

Therefore, further, from another aspect, the present invention providesa method for inhibiting or treating itchiness of the eyes, includingcontacting an aqueous ophthalmic composition having a pH of 7 or more,containing a terpenoid and zinc chloride, with the cornea and/orconjunctiva.

In these methods, use, and compositions, so long as a terpenoid and zincchloride are co-present in the aqueous ophthalmic composition, and theorder of addition of those components are not particularly limited. Aterpenoid and zinc chloride may be those that can be combined in theaqueous ophthalmic composition of the present invention, and amountsthereof may be amounts that can be combined in the aqueous ophthalmiccomposition of the present invention. Also, the kinds and contents ofeach of the components to be combined in the aqueous ophthalmiccomposition, the kinds and contents of the other components to becombined, formulation forms of the composition, and the like are thesame as the aqueous ophthalmic composition of the present invention.

4. Method for Inhibiting Discharges from the Eyes

Further, as mentioned above, by providing an aqueous ophthalmiccomposition having a pH of 7 or more, containing zinc chloride togetherwith a terpenoid, an action for inhibiting discharges from the eyes canbe given to the aqueous ophthalmic composition.

Accordingly, from another aspect, the present invention provides amethod for providing an action for inhibiting discharges from the eyesto an aqueous ophthalmic composition having a pH of 7 or more, includingcombining in the aqueous ophthalmic composition a terpenoid and zincchloride.

Further, from another aspect, the present invention provides use of aterpenoid and zinc chloride, in the manufacture of an aqueous ophthalmiccomposition having a pH of 7 or more, containing a terpenoid and zincchloride, the aqueous composition having an inhibitory action fordischarges from the eyes.

Further, from another aspect, the present invention provides use of acomposition having a pH of 7 or more, containing a terpenoid and zincchloride, as an aqueous ophthalmic composition having an inhibitoryaction for discharges from the eyes.

Further, from another aspect, the present invention provides an aqueouscomposition having a pH of 7 or more, containing a terpenoid and zincchloride, for use in an aqueous ophthalmic composition having aninhibitory action for discharges from the eyes.

In addition, as mentioned above, by contacting an aqueous ophthalmiccomposition of the present invention with the cornea and/or conjunctivaby a method such as eye dropping or washing eyes using the compositionas eye drops or eyewashes, the discharges from the eyes can beinhibited, so that ease in opening eyes, ease in blinking, blurriness ofeyes, appreciative appearance of eyes or the like can be ameliorated.

Therefore, further, from another aspect, the present invention providesa method for inhibiting discharges from the eyes, including contactingan aqueous ophthalmic composition having a pH of 7 or more, containing aterpenoid and zinc chloride, with the cornea and/or conjunctiva.

In these methods, use, and compositions, so long as a terpenoid and zincchloride are co-present in the aqueous ophthalmic composition, the orderof addition of those components is not particularly limited. A terpenoidand zinc chloride may be those that can be combined in the aqueousophthalmic composition of the present invention, and amounts thereof maybe amount that can be combined in the aqueous ophthalmic composition ofthe present invention. Also, the kinds and contents of each of thecomponents to be combined in the aqueous ophthalmic composition, thekinds and contents of the other components to be combined, formulationforms of the composition, and the like are the same as the aqueousophthalmic composition of the present invention.

EXAMPLES

The present invention will be described in detail hereinbelow by meansof Examples and Test Examples, without intending to limit the presentinvention to these Examples and the like.

Test Example 1 Inhibition for Adsorption of Terpenoid

Each of the aqueous ophthalmic compositions of Comparative Examples 1 to7 and Examples 1 and 2 having a composition as listed in Table 1 wasprepared, and 8 mL each was dispensed in a 10 mL eye drop container madeof polyethylene terephthalate (hereinafter also referred to as “PET”).Thereafter, a nozzle made of polyethylene (hereinafter also referred toas “PE”) and a cap were fitted thereto. The units for the contentproportions of the components in Table 1 are w/v %.

Next, these containers were allowed to stand in a thermostat held at 60°C. for one week. Here, “allowed (allowing) to stand” refers to a stateof allowing to stand without applying shaking. The content of thel-menthol in the test solution immediately after the preparation and thecontent after allowing the test solution to stand at 60° C. for one weekwere measured according to a conventional method using gaschromatography.

The residual rate of l-menthol in the test solution (formula (1)) wascalculated in accordance with the following formula (1).

$\begin{matrix}{{{Residual}\mspace{14mu} {Rate}\mspace{14mu} (\%)} = {\frac{\begin{matrix}{1\text{-}{Menthol}\mspace{14mu} {Content}\mspace{14mu} {After}\mspace{14mu} {Allowing}} \\{{to}\mspace{14mu} {Stand}\mspace{14mu} {at}\mspace{14mu} 60{^\circ}\mspace{14mu} {C.\mspace{14mu} {for}}\mspace{14mu} {One}\mspace{14mu} {Week}}\end{matrix}}{\begin{matrix}{{1\text{-}{Menthol}\mspace{14mu} {Content}}\mspace{11mu}} \\{\; {{Immediately}\mspace{14mu} {After}\mspace{14mu} {the}\mspace{14mu} {Preparation}}}\end{matrix}} \times 100}} & {{formula}\mspace{14mu} (1)}\end{matrix}$

Also, as to each of Examples 1 and 2, and Comparative Examples 2, 3, 5and 7, an aqueous ophthalmic composition which does not contain a zinccompound, but a composition of all other components and pH are identicalwas used as a corresponding Comparative Example, and the rate ofinhibiting adsorption of l-menthol to the container was calculated inaccordance with the following formulas (2) and (3). Concretely, as thecorresponding Comparative Example, one that corresponds to ComparativeExamples 2 and 3 is Comparative Example 1, one that corresponds toExample 1 and Comparative Example 5 is Comparative Example 4, and onethat corresponds to Example 2 and Comparative Example 7 is ComparativeExample 6.

$\begin{matrix}{{{Rate}\mspace{14mu} {of}\mspace{14mu} {Adsorption}\mspace{14mu} {of}\mspace{14mu} 1\text{-}{Menthol}\mspace{14mu} {to}\mspace{14mu} {the}\mspace{14mu} {Container}\mspace{14mu} (\%)} = \; {{100(\%)} - {{Residual}\mspace{14mu} {Rate}\mspace{14mu} (\%)}}} & {{formula}\mspace{14mu} (2)} \\{{{Rate}\mspace{14mu} {of}\mspace{14mu} {Inhibiting}\mspace{14mu} {Adsorption}\mspace{14mu} {of}\mspace{14mu} 1\text{-}{Menthol}\mspace{14mu} (\%)} = {\frac{\begin{matrix}{{Rate}\mspace{14mu} {of}\mspace{14mu} {Adsorption}\mspace{14mu} (\%)\mspace{14mu} {of}\mspace{14mu} {Corresponding}} \\{{{Comparative}\mspace{14mu} {Example}} - {{Rate}\mspace{14mu} {of}\mspace{14mu} {Adsorption}\mspace{14mu} (\%)}}\end{matrix}}{\begin{matrix}{{Rate}\mspace{14mu} {of}\mspace{14mu} {Adsorption}\mspace{14mu} (\%)\mspace{14mu} {of}\mspace{14mu} {Corresponding}} \\{{Comparative}\mspace{14mu} {Example}}\end{matrix}} \times 100}} & {{formula}\mspace{14mu} (3)}\end{matrix}$

The results are shown in the following Table 1.

TABLE 1 Comp. Comp. Comp. Comp. Comp. Comp. Comp. Test Solution Name Ex.1 Ex. 2 Ex. 3 Ex. 4 Ex. 1 Ex. 5 Ex. 6 Ex. 2 Ex. 7 Zinc Chloride — 0.01 —— 0.01 — — 0.01 — Zinc Sulfate — — 0.01 — — 0.01 — — 0.01 l-Menthol0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 Polysorbate 800.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Hydrochloric Acid q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. Sodium Hydroxide q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. Purified Water q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. pH (r.t.) 6.5 6.5 6.5 7 7 7 8 8 8 Rate of Adsorption 29.529.3 30.2 32.3 29.1 32.1 41.3 34.8 43.0 of l-Menthol to Container (%)Rate of Inhibiting — 0.7 −2.4 — 9.91 0.6 — 15.7 −4.1 Adsorption ofl-Menthol (%)

As is clear from the results of Comparative Examples 1 to 3 in Table 1,as to the aqueous ophthalmic composition having a pH of 6.5, when thecompositions containing zinc chloride or zinc sulfate and compositionsnot containing them are compared, the aqueous ophthalmic compositionswere found to have hardly any differences in the rate of adsorption ofl-menthol, and were not found to have a great difference in the rate ofinhibiting adsorption of l-menthol by combining the zinc compound, sothat the adsorption of l-menthol to a container was not inhibited bycombining the zinc compound.

On the other hand, as is clear from the results of Comparative Examples4 and 5 and Example 1, in the aqueous ophthalmic compositions having apH of 7, the aqueous ophthalmic compositions were found to have hardlyany differences in the rate of adsorption of l-menthol between thecomposition not containing both of zinc chloride and zinc sulfate andthe composition containing zinc sulfate. However, the compositioncontaining zinc chloride was found to have a decreased rate ofadsorption of l-menthol, and a greatly improved rate of inhibitingadsorption of l-menthol, so that that the inhibition of adsorption ofl-menthol to a container could be confirmed.

Also, from the results of Comparative Examples 6 and 7 and Example 2,similar results were found for the aqueous ophthalmic composition havinga pH of 8.

In addition, the higher the pH, the higher the rate of adsorption ofl-menthol to a container, so that the disadvantages were clarified to begreater.

Accordingly, it could be confirmed that by combining zinc chloride in anaqueous ophthalmic composition having a pH of 7 or more, the adsorptionof l-menthol to a container can be inhibited.

Test Example 2 Inhibition 2 for Adsorption of Terpenoid

Test solutions were prepared in accordance with a formulation as listedin Tables 2 and 3, the content of a terpenoid (1-menthol or d-borneol)was measured in the same manner as in Test Example 1, and the residualrate of the terpenoid in the test solution was calculated in accordancewith the formula (1), provided that in Comparative Example 12 andExample 9, a container made of polyethylene was used as an eye dropcontainer in place of a container made of PET. In addition, the rate ofinhibiting adsorption of the terpenoid to a container was calculated inaccordance with the formulas (2) and (3). The results are also showntogether in Tables 2 and 3. The units for the content proportions of thecomponents in Tables 2 and 3 are w/v %.

The phrase “corresponding Comparative Examples” as used hereinconcretely refers to an aqueous ophthalmic composition which does notcontain a zinc compound, but a composition of all other components andpH are identical, or refers to an aqueous ophthalmic composition whichdoes not contain zinc chloride and a polymeric compound, but acomposition of all other components and pH are identical, and thecorrespondences are concretely as in the following Table 4.

TABLE 2 Comp. Comp. Comp. Comp. Comp. Test Solution Name Ex. 8 Ex. 9 Ex.10 Ex. 11 Ex. 12 l-Menthol 0.015 0.005 — 0.01 0.015 d-Borneol — — 0.005— — Polysorbate 80 0.05 0.05 0.05 0.04 0.05 Hydroxyethyl — — 1 0.01 —Cellulose Hydrochloric Acid q.s. q.s. q.s. q.s. q.s. Sodium Hydroxideq.s. q.s. q.s. q.s. q.s. Purified Water bal. bal. bal. bal. bal. pH(r.t.) 7.8 7.8 7.8 7.8 7.8

TABLE 3 Test Solution Name Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9Zinc Chloride 0.003 0.0001 0.003 0.0001 0.0005  0.008 0.003 l-Menthol0.015 0.005 0.015 0.015 — 0.01 0.015 d-Borneol — — — — 0.005 — —Polysorbate 80 0.05  0.05 0.05 0.05 0.05 0.04 0.05 Hypromellose — — —0.6 — — — Hydroxyethyl — — 1 — 1 0.01 — Cellulose Hydrochloric Acid q.s.q.s. q.s. q.s. q.s. q.s. q.s. Sodium Hydroxide q.s. q.s. q.s. q.s. q.s.q.s. q.s. Purified Water bal. bal. bal. bal. bal. bal. bal. pH 7.8  7.87.8 7.8 7.8 7.8  7.8 Rate of Inhibiting 4.1  3.1 8.9 20.8 12.7 3.1  2.0Adsorption of Terpenoid (%)

TABLE 4 Corresponding Example Comparative Examples Examples 3, 5, 6Comparative Example 8 Example 4 Comparative Example 9 Example 7Comparative Example 10 Example 8 Comparative Example 11 Example 9Comparative Example 12

As is clear from Tables 2 and 3, the test solutions of Examples 3 to 9containing zinc chloride and a terpenoid showed greatly improved ratesof inhibiting adsorption of a terpenoid, as compared to the testsolutions of corresponding Comparative Examples containing a terpenoidwithout containing zinc chloride, so that it could be confirmed thatadsorption of a terpenoid to a container was inhibited by combining zincchloride. In addition, the test solutions of Examples 5, 6 and 7 furthercontaining a polymeric compound in addition to zinc chloride and aterpenoid showed even higher rates of inhibiting adsorption of aterpenoid. Also, as to a case of Example 9 using a container made ofpolyethylene, an effect of inhibiting adsorption of a terpenoid to acontainer was found in the same manner as the case using a PETcontainer.

Test Example 3 Inhibition for Histamine Release

Rat basophil leukemia cell line (RBL-2H3) suspended in a DMEM medium(manufactured by Invitrogen) supplemented with a 10% by volume fetalbovine serum (manufactured by Invitrogen) was seeded to a 96-wellmicrotiter plate (manufactured by Corning) at a density of 1.4×10⁵cells/cm², and cultured at 37° C. under 5% CO₂ for 24 hours. Thereafter,the culture supernatant was removed by suction, a test solution aslisted in Table 5 was added thereto in a volume of 0.1 ml each per well,and the cultured cells were incubated at 37° C. for 1 hour under 5% CO₂.Thereafter, the culture supernatant was removed by suction, PIPES buffersupplemented with a reagent A23187 (manufactured by SIGMA) so as to havea concentration of 10 μM was added thereto in a volume of 0.2 ml eachper well, and the cultured cells were incubated at 37° C. for 30 minutesunder 5% CO₂. Here, as the PIPES buffer, the following was used: pH 7.2,composition: 0.1 w/v % bovine serum albumin (manufactured by SIGMA),CaCl₂.2H₂O 3.0 mM, MgCl₂.6H₂O 0.40 mM, KCl 7.38 mM, NaCl 118.93 mM,D(+)-Glucose 5.60 mM, 25 mM PIPES (Piperazine-1,4-bis(2-ethanesulfonicacid)), manufactured by DOJINDO LABORATORIES.

The supernatant of each well was collected, and the concentration ofhistamine was quantified using an ELISA kit (manufactured by OxfordBiochemical Research).

Also, as a control, a test was conducted in the same manner as themethod mentioned above to quantify a histamine concentration, exceptthat the PIPES buffer was added to carry out incubation in place of theprocedures in which a test solution was added to carry out incubation.

Further, as blank, a test was conducted in the same manner as thecontrol to quantify a histamine concentration, except that PIPES buffernot supplemented with A23187 was added to carry out incubation in placeof the procedures in which PIPES buffer supplemented with A23187 wasadded to carry out incubation.

Values resultant from subtracting the histamine concentration of theblank from the histamine concentrations of each sample and the controlare defined as a true histamine concentration of each sample and a truehistamine concentration of the control, respectively. Using the truehistamine concentration of each sample and the true histamineconcentration of the control obtained, the rate of inhibiting histaminerelease (%) was calculated in accordance with the following formula (4).

$\begin{matrix}{{{Rate}\mspace{14mu} {of}\mspace{14mu} {Inhibiting}\mspace{14mu} {Histamine}\mspace{14mu} {Release}\mspace{14mu} (\%)} = {\left\{ {1 - \frac{\begin{matrix}{{True}\mspace{14mu} {Histamine}\mspace{14mu} {Concentration}\mspace{14mu} {of}} \\{{Each}\mspace{14mu} {Test}\mspace{14mu} {Solution}}\end{matrix}}{{True}\mspace{14mu} {Histamine}\mspace{14mu} {Concentration}\mspace{14mu} {of}\mspace{14mu} {Control}}} \right\} \times 100}} & (4)\end{matrix}$

Further, based on the rate of inhibiting histamine release calculatedaccording to the above method, as to Comparative Examples 14 to 16 usinga test solution having a pH of 6.5, an increased amount of rate ofinhibiting histamine release based on Comparative Example 13 wascalculated in accordance with the following formula (5), on the basis ofthe rate of inhibiting histamine release in Comparative Example 13 usinga test solution having a pH of 6.5, not containing both of zinc chlorideand 1-menthol. As to Comparative Examples 18 and 19 and Example 10 usinga test solution having a pH of 7.0, an increased amount of rate ofinhibiting histamine release based on Comparative Example 17 wascalculated in accordance with the following formula (5), on the basis ofthe rate of inhibiting histamine release in Comparative Example 17 usinga test solution having a pH of 7.0, not containing both of zinc chlorideand 1-menthol. The results are together shown in Table 5.

$\begin{matrix}{{{Increased}\mspace{14mu} {Amount}\mspace{14mu} {of}\mspace{14mu} {Rate}\mspace{14mu} {of}\mspace{14mu} {Inhibiting}\mspace{14mu} {Histamine}\mspace{14mu} {Release}\mspace{14mu} (\%)} = {{{Rate}\mspace{14mu} {of}\mspace{14mu} {Inhibiting}\mspace{14mu} {Histamine}\mspace{14mu} {Release}\mspace{14mu} {in}\mspace{14mu} {Comparative}\mspace{14mu} {Example}\mspace{14mu} {or}\mspace{14mu} {Example}} - {{Rate}\mspace{14mu} {of}\mspace{14mu} {Inhibiting}\mspace{14mu} {Histamine}\mspace{14mu} {Release}\mspace{14mu} {in}\mspace{14mu} {Comparative}\mspace{14mu} {Example}\mspace{14mu} 13\mspace{14mu} {or}\mspace{14mu} {Comparative}\mspace{14mu} {Example}\mspace{14mu} 17}}} & (5)\end{matrix}$

Here, as the standards of the components used in the test, zinc chlorideis a reagent manufactured by Wako Pure Chemical Industries, Ltd., andl-menthol is a reagent manufactured by Wako Pure Chemical Industries,Ltd. Also, units of the content proportions of the components in Table 5are w/v %.

TABLE 5 Comp. Comp. Comp. Comp. Comp. Comp. Comp. Ex. 13 Ex. 14 Ex. 15Ex. 16 Ex. 17 Ex. 18 Ex. 19 Ex. 10 Zinc Chloride — —  0.001 0.001 — — 0.001  0.001 l-Menthol —  0.01 — 0.01 —  0.01 —  0.01 Polysorbate 80 0.03  0.03  0.03 0.03  0.03  0.03  0.03  0.03 Boric acid 0.2 0.2 0.20.2 0.2 0.2 0.2 0.2 Borax q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. SodiumChloride 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Purified Water q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. pH 6.5 6.5 6.5 6.5 7.0 7.0 7.0 7.0 IncreasedAmount of — −16.7  −4.4  −12.5 — — — — Rate of Inhibiting HistamineRelease Based on Comp. Ex. 13 (%) Increased Amount of — — — — — −9.8 4.5  10.6 Rate of Inhibiting Histamine Release Based on Comp. Ex. 17 (%)

As is clear from Table 5, Comparative Examples 14 and 18 using a testsolution in which menthol was combined in the test solution ofComparative Example 13 or 17 were both likely to have lowered inhibitoryeffects for histamine release, as compared to that of ComparativeExample 13 or 17. Further, Comparative Example 16 using a test solutionhaving a pH of 6.5 in which menthol and zinc chloride were combined inthe test solution of Comparative Example 13 was hardly found to have anyimprovements in inhibitory effects for histamine release.

By contrast, Example 10 using a test solution having a pH of 7.0 inwhich menthol and zinc chloride were combined in the test solution ofComparative Example 17 had remarkable improvements in the effects ofinhibiting histamine release, and exhibited high effects of inhibitinghistamine release.

Test Example 4 Inhibitory Test for Discharges from the Eyes

Test solutions were prepared in accordance with a formulation as listedin Table 6 and 7, and filled in an eye drop container made of PET togive a test sample. A tested individual was instilled into the eyes twokinds of test samples as one set, one set of the test sample instillinginto the right eye, and the other set instilling into the left eye, oneset per day, five times a day, 2 drops each time (n=10). Here, one kindof the test sample was always instilled into the identical eye, and theintervals of instillations between each time were kept one or morehours. After 2 hours or more from the fifth instillation into the eyes,the amount of discharges from the eyes which the tested individualsubjectively sensed was evaluated in accordance with a visual analoguescale method (VAS method). In other words, on a straight line of 10 cmin length, the left end of the straight line, i.e. a point at 0 cm isdefined as “no discharges from the eyes being found,” and the right endof the straight line, i.e. a point at 10 cm is defined as “maximumamount of discharges from the eyes which was experienced in the pastbeing found,” the tested individual was asked to show one point on thestraight line that corresponds to the amount of discharges from the eyeswhich is subjectively sensed in the eyes after the instillation into theeyes of each of test samples, the distance (cm) from the point at 0 cmwas measured and defined as scores on the amount of discharges from theeyes. The results are together shown in Tables 6 and 7. The units of thecontent proportions of the components in Tables 6 and 7 are w/v %.

TABLE 6 Name of Set Set A Set B Set C Set D Right Eye/Left Eye RightLeft Right Left Right Left Right Left Eye Eye Eye Eye Eye Eye Eye EyeTest Solution Name Comp. Comp. Comp. Comp. Comp. Ex. 20 Ex. 21 Ex. 22Ex. 11 Ex. 23 Ex. 12 Ex. 24 Ex. 13 Zinc Chloride —  0.002 —  0.002 —0.002 — 0.002 l-Menthol — —  0.05  0.05  0.01 0.01 0.01 0.01 Polysorbate80  0.04  0.04 0.2 0.2  0.04 0.04 0.04 0.04 Chlorobutanol  0.35  0.35Hydroxyethyl — — — — — — 0.01 0.01 Cellulose Boric Acid 1   1   1   1  1   1 1 1 Sodium Chloride 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Borax q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. Purified Water q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. pH 7.2 7.2 7.2 7.2 7.2 7.2 7.2 7.2 Amount of 6.4 5.84.9 3.4 5.5 3.5 6.7 2.5 Discharges from the Eyes (Average)

TABLE 7 Name of Set Set E Right Eye/Left Eye Right Eye Left Eye TestSolution Name Comp. Ex. 20 Comp. Ex. 25 Zinc Chloride — 0.002 l-Menthol— 0.01 Polysorbate 80 0.04 0.04 Boric Acid 1 1 Sodium Chloride 0.4 0.4Borax q.s. q.s. Purified Water q.s. q.s. pH 7.2 6.0 Amount of Discharges6.4 7.0 from the Eyes (Average)

As is clear from Tables 6 and 7, the test solutions having a pH of 7.2,containing zinc chloride and menthol of Examples 11 to 13 were found tohave remarkable inhibitory effects of the discharges from the eyes.Particularly, as is clear from comparison of Comparative 21 and 23 withExample 12, test solutions containing either one of zinc chloride ormenthol of Comparative Examples 21 and 23 were found to have a slightlyinhibitory effect of discharges from the eyes. By contrast, a testsolution concomitantly containing both zinc chloride and menthol ofExample 12 was found to have remarkable inhibitory effects of dischargesfrom the eyes.

Incidentally, a test solution having a pH of 6.0 of Comparative Example25 was not found to have inhibitory effects of discharges from the eyes,even when containing zinc chloride and menthol.

1. An aqueous ophthalmic composition having a pH of 7 or more,comprising a terpenoid and zinc chloride.
 2. The aqueous ophthalmiccomposition according to claim 1, wherein the terpenoid is at least onemember selected from the group consisting of menthol, menthone, camphor,borneol, and geraniol.
 3. The aqueous ophthalmic composition accordingto claim 1 or 2, wherein the composition is housed in a container madeof a material comprising at least one plastic selected from the groupconsisting of polyethylene terephthalate resins, polypropylene resins,polyethylene resins, and polyethylene naphthalate resins.
 4. A methodfor inhibiting adsorption of a terpenoid in an aqueous ophthalmiccomposition having a pH of 7 or more to a container, comprisingcombining in the aqueous ophthalmic composition zinc chloride togetherwith a terpenoid.
 5. A method for enhancing an inhibitory action forhistamine release of an aqueous ophthalmic composition having a pH of 7or more, comprising combining in the aqueous ophthalmic composition zincchloride together with a terpenoid.
 6. A method for giving an inhibitoryaction for discharges from the eyes to an aqueous ophthalmic compositionhaving a pH of 7 or more, comprising combining in the aqueous ophthalmiccomposition zinc chloride together with a terpenoid.